HSP72 protects against obesity-induced insulin resistance

doi:10.1073/pnas.0705799105

HSP72 protects against obesity-induced insulin resistance

*Cellular and Molecular Metabolism Laboratory,
^‡Clinical Physiology, and
^§Human Vascular Biology, Baker Heart Research Institute, Prahran, P.O. Box 6492, Victoria 8008, Australia;
^†Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, CA 92093;
^¶Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, 6726, Szeged, Hungary;
^‖Department of Physiology and the Cardiovascular Institute, Loyola University Medical Center, Maywood, IL 60153;
**St. Vincent's Institute of Medical Research and the Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia;
^††Department of Endocrinology, University Colorado Health Sciences Center, Aurora, CO 80045; and
^‡‡David Geffen School of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, CA 90095

Edited by Michael Karin, University of California at San Diego School of Medicine, La Jolla, CA, and approved December 3, 2007 (received for review June 20, 2007)

Abstract

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of κB kinase, and tumor necrosis factor-α, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Footnotes

^§§To whom correspondence may be addressed at the ‡‡ address. E-mail: ahevener{at}mednet.ucla.edu
^¶¶To whom correspondence may be addressed at:
Cellular and Molecular Metabolism Laboratory, Diabetes and Metabolism Division, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Road Central, VIC, 8008, Australia.
E-mail: mark.febbraio{at}baker.edu.au
Author contributions: B.A.K., L.V., A.H., and M.A.F. designed research; J.C., A.-K.N., D.C.H., S.J.D., I.H., and A.H. performed research; R.M., P.L.H., and L.V. contributed new reagents/analytic tools; J.C., A.-K.N., D.C.H., A.G.H., M.H.S.C., J.L.M., G.I.L., R.J.S., C.R.B., I.H., M.J.W., and A.H. analyzed data; and J.C., A.H., and M.A.F. wrote the paper.
Conflict of interest statement: We obtained the drug BGP-15 from N-Gene R&D Inc., and I.H., L.V., and M.A.F. have a financial interest in this company.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705799105/DC1.
Freely available online through the PNAS open access option.